14-Substituted Diquinothiazines as a New Group of Anticancer Agents

Małgorzata Jeleń; Krystian Pluta; Małgorzata Szmielew; Beata Morak-Młodawska; Kinga Herman; Klaudia Giercuszkiewicz; Anna Kasprzycka; Magdalena Skonieczna

doi:10.3390/molecules28073248

14-Substituted Diquinothiazines as a New Group of Anticancer Agents

Molecules. 2023 Apr 5;28(7):3248. doi: 10.3390/molecules28073248.

Authors

Małgorzata Jeleń¹, Krystian Pluta¹, Małgorzata Szmielew¹, Beata Morak-Młodawska¹, Kinga Herman², Klaudia Giercuszkiewicz³, Anna Kasprzycka^{2

4}, Magdalena Skonieczna^{3

4}

Affiliations

¹ Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, The Medical University of Silesia, Jagiellońska 4, 41-200 Sosnowiec, Poland.
² Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Krzywoustego Street 4, 44-100 Gliwice, Poland.
³ Department of Systems Biology and Engineering, The Silesian University of Technology, Akademicka Street 16, 44-100 Gliwice, Poland.
⁴ Centre of Biotechnology, Silesian University of Technology, Krzywoustego Street 8, 44-100 Gliwice, Poland.

Abstract

A series of novel double-angularly condensed diquinothiazines with aminoalkyl, amidoalkyl, sulfonamidoalkyl, and substituted phenyl groups was designed, synthesized, and evaluated for their anticancer activity against four selected human tumor cell lines (HTC116, SH-SY5Y, A549, and H1299). The cytotoxicity of the novel diquinothiazines was investigated against BEAS-2B cells. The activities of the compounds were compared to etoposide. Among them, compounds with aminoalkyl and phenyl groups showed excellent broad-spectrum anticancer activity. The most active 14-(methylthiophenyl)diquinothiazine, 3c, showed low cytotoxicity against BEAS-2B cells and high activity against tumor cell lines HTC116, SH-SY5Y, A549, and H1299, with IC₅₀ values of 2.3 µM, 2.7 µM, 17.2 µM, and 2.7 µM, respectively (etopiside 8.6 µM, 3.9 µM, 44.8 µM, and 0.6, respectively). Live long-term microscopic observations of cell survival using the starting molecule M0 were also performed. Flow cytometry showed the proapoptotic effects of the studied diquinothiazines. Inhibition of the cell cycle in the S phase was observed, which is associated with damage to nucleic acids and connected to DNA replication arrest.

Keywords: anticancer activity; apoptosis; cell cycle arrest; cytotoxicity; diazaphenothiazines; diquinothiazines; phenothiazines.

MeSH terms

Antineoplastic Agents* / pharmacology
Apoptosis
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Neuroblastoma*
Structure-Activity Relationship

Substances

Antineoplastic Agents

Grants and funding

Małgorzata Jeleń was supported by a research subsidy from The Medical University of Silesia in Katowice, grant PCN-1-043K/2/F. Beata Morak-Młodawska was supported by a research subsidy from The Medical University of Silesia in Katowice, grant PCN-1-041/K/2/F. Total synthesis, structural analysis, and the APC were funded by The Medical University of Silesia in Katowice, grant PCN-1-043/K/2/F and PCN-1-041/K/2/F. M.S. was supported by research subsidy No 02/040/BK_23/1035 from the Silesian University of Technology in Gliwice, Poland. K.G. and K.H. were supported by a research subsidy for students from the European Union from the European Social Fund in the framework of the project “Silesian University of Technology as a Center of Modern Education based on research and innovation” POWR.03.05.00-00-Z098/17 (5th and 7th edition of PBL student’s projects, respectively).